Effects of school-based physical activity and multi-micronutrient supplementation intervention on growth, health and well-being of schoolchildren ...
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Gerber et al. Trials (2020) 21:22
https://doi.org/10.1186/s13063-019-3883-5
STUDY PROTOCOL Open Access
Effects of school-based physical activity
and multi-micronutrient supplementation
intervention on growth, health and well-
being of schoolchildren in three African
countries: the KaziAfya cluster randomised
controlled trial protocol with a 2 × 2
factorial design
Markus Gerber1* , Serge A. Ayekoé2, Johanna Beckmann1, Bassirou Bonfoh3,4,5, Jean T. Coulibaly3,4,5,6,
Dao Daouda5, Rosa du Randt7, Lina Finda8, Stefanie Gall1, Getrud J. Mollel8, Christin Lang1, Kurt Z. Long1,3,4,
Sebastian Ludyga1, Honorati Masanja8, Ivan Müller1, Siphesihle Nqweniso7, Fredros Okumu8,
Nicole Probst-Hensch3,4, Uwe Pühse1, Peter Steinmann3,4, Sylvain G. Traoré5,9, Cheryl Walter7 and Jürg Utzinger3,4
Abstract
Background: In low- and middle-income countries, infectious diseases remain a key public health issue.
Additionally, non-communicable diseases are a rapidly growing public health problem that impose a considerable
burden on population health. One way to address this dual disease burden, is to incorporate (lifestyle) health
promotion measures within the education sector. In the planned study, we will (i) assess and compare physical
activity, physical fitness, micronutrient status, body composition, infections with soil-transmitted helminths,
Schistosoma mansoni, malaria, inflammatory and cardiovascular health risk markers, cognitive function, health-
related quality of life, and sleep in schoolchildren in Côte d’Ivoire, South Africa and Tanzania. We will (ii) determine
the bi- and multivariate associations between these variables and (iii) examine the effects of a school-based health
intervention that consists of physical activity, multi-micronutrient supplementation, or both.
Methods: Assuming that no interaction occurs between the two interventions (physical activity and multi-
micronutrient supplementation), the study is designed as a cluster-randomised, placebo-controlled trial with a 2 × 2
factorial design. Data will be obtained at three time points: at baseline and at 9 months and 21 months after the
baseline assessment. In each country, 1320 primary schoolchildren from grades 1–4 will be recruited. In each
school, classes will be randomly assigned to one of four interventions: (i) physical activity; (ii) multi-micronutrient
supplementation; (iii) physical activity plus multi-micronutrient supplementation; and (iv) no intervention, which will
serve as the control. A placebo product will be given to all children who do not receive multi-micronutrient
supplementation. After obtaining written informed consent from the parents/guardians, the children will be
(Continued on next page)
* Correspondence: markus.gerber@unibas.ch
1
Department of Sport, Exercise and Health, University of Basel, Basel,
Switzerland
Full list of author information is available at the end of the article
© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Gerber et al. Trials (2020) 21:22 Page 2 of 17 (Continued from previous page) subjected to anthropometric, clinical, parasitological and physiological assessments. Additionally, fitness tests will be performed, and children will be invited to wear an accelerometer device for 7 days to objectively assess their physical activity. Children infected with S. mansoni and soil-transmitted helminths will receive deworming drugs according to national policies. Health and nutrition education will be provided to the whole study population independently of the study arm allocation. Discussion: The study builds on the experience and lessons of a previous study conducted in South Africa. It involves three African countries with different social-ecological contexts to investigate whether results are generalisable across the continent. Trial registration: The study was registered on August 9, 2018, with ISRCTN. https://doi.org/10.1186/ ISRCTN29534081. Keywords: Children, Côte d’Ivoire, Dual disease burden, Health, Multi-micronutrient supplementation, Placebo, Physical activity, South Africa, Tanzania, Well-being Background undernutrition as a risk factor [2, 10]. Consequently, Ensuring healthy lives and promoting well-being among children are at an increased risk of compromised health children is a complex and challenging endeavour. In- due to a dual burden of diseases, which may hamper deed, children’s health depends on cultural, environmen- their development and well-being [8, 11]. The drivers of tal, genetic and socioeconomic factors as well as current this dual burden may relate to the shift in dietary con- living conditions and social and community networks sumption patterns and energy expenditure as these [1]. In low- and middle-income countries (LMICs), in- countries pass through rapid nutritional and epidemio- fectious diseases remain a key public health issue, nega- logical changes. This trend might also result from the ef- tively impacting children’s physical and cognitive fect that underlying micronutrient deficiencies have on development [2]. For example, more than a billion childhood stunting and changes in body composition, people are infected with parasitic worms (helminths) [3]. leading to greater adiposity and possibly contributing to Helminth infections can cause abdominal pain, anaemia long-term risks of obesity [12–15]. This dual burden and (bloody) diarrhoea and might impair cognitive and constitutes a challenge for health systems in Africa and physical development [4], resulting in reduced fitness elsewhere. Although many children are still affected by and work productivity [5]. Moreover, helminth infec- infectious diseases, at a young age, they may already tions can have a negative impact on a child’s nutritional have developed risk factors predisposing them to NCDs status [6]. A deprived socioeconomic status (SES) of par- in early adulthood [16, 17]. ents can put children at risk of malnutrition and growth Given that (i) childhood physical inactivity is an inde- retardation. Malnutrition has been found to be associ- pendent risk factor for NCDs, which can lead to poor ated with stunting and poor cognitive development, health outcomes in later life [18–20] and that (ii) micronu- thereby resulting in low IQ, cognitive delays and prob- trient status influences health and body composition and lems with motor development. This, in turn, can cause subsequently the development of obesity and obesity- problems with a child’s ability to concentrate, process related conditions [21], one plausible strategy is to focus on information and focus on school work [7]. Children the promotion of physical activity and multi-micronutrient from low SES families are also less likely to have access supplementation through school-based health promotion to health care or health insurance and are more prone programmes. School-based physical activity interventions to be absent from school, which may have negative con- are worthwhile because a considerable amount of children’s sequences on their academic performance. These defi- daily physical activity is acquired during school hours [22]. ciencies can prevent school-aged children from realising Moreover, school-based physical activity programmes are their full potential and perpetuate a vicious cycle of pov- generally effective in increasing physical activity and phys- erty and poor health. ical fitness in children and adolescents aged 6–18 years Non-communicable diseases (NCDs) are a rapidly [23]. For instance, a randomised controlled trial with Swiss growing public health problem that impose a consider- primary schoolchildren (first and fifth graders) showed that able burden on population health [8]. New research re- physical activity and fitness could be significantly improved vealed that African populations have moved towards a with a 1-year, school-based, physical activity intervention, disease profile similar to Western countries, with in- whereas adiposity could be decreased [24]. creasing proportions of deaths attributed to chronic, An attempt to increase health literacy in South African lifestyle-related diseases [9] and overweight, replacing children from disadvantaged schools was undertaken in
Gerber et al. Trials (2020) 21:22 Page 3 of 17 the ‘Disease, Activity and Schoolchildren’s Health’ result in a decrease in fat mass and increased lean body (DASH) project [3]. The study primarily focused on the mass. development of healthy school environments by imple- menting a series of clearly defined and standardised Specific aims of the study intramural measures. The developed intervention toolkit There are three interrelated specific aims that will be ad- was pilot-tested among fourth graders in disadvantaged dressed in the planned study: primary schools in Port Elizabeth, South Africa. The preliminary findings suggest that (i) the prevalence of To assess and compare physical activity, physical parasitic worm infection was high in several schools fitness, micronutrient status, body composition, [25]; (ii) children infected with soil-transmitted hel- infections with soil-transmitted helminths, S. man- minths had lower maximal oxygen uptake compared to soni, malaria, inflammatory and cardiovascular their non-infected peers [26]; (iii) helminth infections health risk markers, cognitive function, HRQoL, and and low physical fitness were significant predictors of sleep in schoolchildren in Côte d’Ivoire, South Africa low selective attention and poor academic achievement and Tanzania. [27]; (iv) increased levels of physical activity were associ- To determine the bi- and multivariate associations ated with a higher health-related quality of life (HRQoL) that exist among physical activity, physical fitness, [28]; (v) increased physical activity levels were associated micronutrient status, body composition, infections with lower risks of obesity and hypertension, but in- with soil-transmitted helminths, S. mansoni, malaria, creased risk for soil-transmitted helminth infections inflammatory and cardiovascular health risk [29]; and (vi) the DASH physical activity component re- markers, cognitive function, HRQoL, and sleep in sulted in small but significant decreases in the body schoolchildren in the three study countries. mass index (BMI) of the children [30] and had a positive To examine the effects of a school-based health impact on academic performance within one year [31]. intervention (physical activity, multi-micronutrient The intervention teaching material used in the DASH supplementation or both) on physical activity, phys- study was further elaborated and adapted and then ical fitness, micronutrient status, body composition, pilot-tested among schoolchildren in grades 4–7 from infections with soil-transmitted helminths, S. man- two disadvantaged primary schools in Port Elizabeth. soni, malaria, inflammatory and cardiovascular After the pilot-testing, final adaptations were made ac- health risk markers, cognitive function, HRQoL, and cording to the feedback of school teachers, teacher- sleep in schoolchildren in the three study countries. coaches and students. The present study will build on and expand DASH by Additionally, secondary aims are to determine how the implementing this school-based health promotion intervention is perceived by the school principals, programme in two other African countries and by pro- teachers, parents and children, and whether or not the viding multi-micronutrient supplementation. Placing an teachers can be empowered to implement the teaching additional emphasis on multi-micronutrient supplemen- material successfully by themselves. The study also has tation is justified on multiple grounds. First, a recent the potential for highlighting how micronutrient defi- meta-analysis concluded that helminth infections and ciencies may contribute to the observed increases in micronutrient deficiencies are highly prevalent in obesity prevalence, which is on the rise in some African LMICs. Second, a strong relationship exists between hel- countries. minth infections and serum retinol in school-aged chil- Specific hypotheses for each of the outcome variables dren. Third, micronutrient-supplementation randomised were formulated, hereby taking into account existing evi- controlled trials (RCTs) showed a modest, but significant dence from previous studies, mostly carried out with protective effect on helminth infection and reinfection children living in Western societies. These hypotheses rates [32]. Fourth, periodic deworming has not trans- are described in detail in the supplementary material lated into the expected health gains according to recent (see Additional file 1). systematic reviews and meta-analyses [33, 34]. One rea- son for this may be the concurrent problem of malnutri- Methods/Design tion and underlying micronutrient deficiencies, which Study design makes it difficult for children to compensate for delays We assume that no interaction occurs between the two in growth and development that resulted from infectious interventions (physical activity and multi-micronutrient diseases. Thus, multi-micronutrient supplementation supplementation). The study is designed as a cluster ran- might make deworming more effective in terms of a domised, placebo-controlled trial [37] using a 2 × 2 fac- positive health impact. Fifth, as shown in previous stud- torial design to assess the effect of physical activity and ies [35, 36], multi-micronutrient supplementation might multi-micronutrient supplementation on children’s
Gerber et al. Trials (2020) 21:22 Page 4 of 17 growth, health and well-being (Fig. 1). Data will be next section). To ensure allocation concealment, the assessed at three time points (baseline and 9 months and four treatment arms will be determined by a computer- 21 months after the baseline assessment). At baseline, generated code after the baseline assessment. The four children from grades 1–4 (most of them aged 6–10 intervention arms are (i) physical activity; (ii) multi- years) will be recruited. The intervention will span two micronutrient supplementation; (iii) physical activity school years. The project officially started in January plus multi-micronutrient supplementation; and (iv) no 2018. After 9 months of preparation and obtaining eth- specific interventions, which will serve as the control. ical approval from the relevant authorities, interventions Based on the four intervention arms, the main and inter- have been launched in 2019. The project will last until action effects of the two intervention components (phys- December 2021 (see SPIRIT Flow Chart in Additional ical activity and multi-micronutrient supplementation) file 2). will be examined. The study will be carried out in primary schools in the We will provide a placebo product to all children who area of Taabo in south-central Côte d’Ivoire, in Port do not receive multi-micronutrient supplementation. For Elizabeth in the Eastern Cape Province of South Africa, physical activity, controlling with a placebo is not feas- and in Ifakara in the Kilombero district of Tanzania. To ible. Thus, classes not involved in the physical activity obtain an adequate sample size for overweight/obese intervention will follow their routine lesson plans so children, the intervention will not take place in the most that, during the intervention phase, all students will have remote areas but rather in villages that are located in similar amounts of contact with schoolmates and rural (Côte d’Ivoire and Tanzania) or peri-urban (South teachers. To minimise subjective biases, teachers and Africa) settings in the three study countries. local study personnel will be blinded with regard to the In each country, we aim to recruit 1320 children from multi-micronutrient supplementation or placebo tablets. public school classes. Classes will be randomly assigned In case of missing values (e.g. when children drop out to one of four interventions (for more details, see the during the intervention), all analyses will be performed Fig. 1 Overview of the planned study design (Note. MMNS = multi-micronutrient supplementation; PA = physical activity; STH = soil-transmitted helminth; T2 = 9-month follow-up; T3 = 21-month follow-up). All children receive health and nutritional education during the 2-year study period 4
Gerber et al. Trials (2020) 21:22 Page 5 of 17
with and without intention-to-treat [38]. After a thor- (classes). A division of classes (in order to allow individ-
ough dropout analysis, a decision will be made on the ual randomisation) would affect the everyday school life
most suitable method to use to analyse the intention-to- in a negative way and would be considered interruptive
treat effects (e.g. imputation of missing values) [39]. by the teacher staff. As a consequence, our intervention
would not be acceptable to the school principals and
Participants and procedures education authorities.
All children will be recruited in the schools involved in Before baseline data assessment, written informed con-
the project. School authorities will be contacted first. sent will be sought from the parents/guardians of the
Contact with schools is made through the school princi- children. In line with the Ottawa Statement [40], despite
pals. School principals will be informed about the objec- cluster randomisation, we will ask each research partici-
tives, procedures and potential risks and benefits of the pant and his/her parents guardians for informed consent
study. Based on this information, the principals can state before the children and their parents guardians know to
their interest in being part of the project. which cluster they will be allocated. Research assistants
To achieve at least small effects (f = 0.10) in the pri- will explain the purpose and procedures of the study,
mary outcomes (physical activity and micronutrient defi- the expected duration, potential risks and benefits and
ciency) and to take into account the children’s weight any discomfort it may entail for the children. The par-
status (underweight, normal weight, or overweight/ ents/guardians will be provided with a participant infor-
obese), power calculations indicate that a total sample of mation sheet and a consent form describing the study
1096 children is needed per study site (calculations and providing sufficient information to make an in-
based on G*power 3.1: alpha error probability = 0.05, formed decision about whether or not to participate. For
power = 0.80, number of groups = 12 (2x2x3: physical ac- illiterate parents, the information sheet will be read
tivity intervention: yes/no, multi-micronutrient supple- aloud and, if necessary, an oral translation of the infor-
mentation: yes/no; weight status: underweight, normal mation sheet into any of the local languages will be pro-
weight, or overweight), number of measurements = 3). vided. Parents/guardians will be informed that
Assuming a yearly dropout-rate of 10%, the targeted participation is voluntary, data will be handled confiden-
sample size is 1320 children per country at baseline. tially, and withdrawal from the study can occur anytime
Thus, in each country, approximately 330 students will without further obligation, and that withdrawal of con-
be assigned to one of the four intervention arms. sent will not have any negative consequences except for-
After having identified suitable schools, we will going the potential benefits of the allocated intervention.
proceed in two steps to allocate classes to the four inter- After having obtained written informed consent, the par-
vention arms. First, we develop a stratification table to ents/guardians will be asked a few specific questions re-
ensure that each intervention arm will be represented in garding the families’ SES, and the dietary intake
every grade across all schools. We then randomly assign information, sleep and physical activity behaviour of the
the schools to the different strata, as shown in Fig. 2. If a children. Additionally, oral assent will be sought from
school has several classes per grade, the classes will be children before the start of the study.
randomly selected. Given that our intervention takes
place in a school setting, is implemented during official Criteria for inclusion/exclusion
class hours, is integrated in the current curriculum, and School eligibility criteria include (i) public schools from
is provided by the class teachers, we have no choice disadvantaged areas; (ii) facilities for the implementation
other than to randomise the participants in clusters of physical education lessons (free space: lawn, sand or
Fig. 2 Assignment of classes to conditions via stratification to ensure that each intervention arm is represented at each grade across all schools
(Note. PA = physical activity; MMNS = multi-micronutrient supplementation)Gerber et al. Trials (2020) 21:22 Page 6 of 17
concrete ground); and (iii) not engaged in any other re- physical activity opportunities are incorporated into the
search project or clinical trial or located in areas where main school curriculum, including daily in-class activity
governmental nutrition interventions take place. breaks as well as one weekly 40-min playful physical
To be included in the data assessment, children must education lesson and one 40-min moving-to-music
accomplish the following inclusion criteria: (i) attend lesson. These measures are designed towards improving
grades 1–4 at baseline; (ii) aged 6–12 years at baseline; children’s physical activity levels and positively affecting
(iii) have written informed consent from their parents/ their school satisfaction and psychosocial well-being.
guardians; (iv) not participating in other research pro- The intervention materials presented above were pilot-
jects or clinical trials; (v) not participating in any food/ tested in 2015 and 2016 in the DASH study with fourth
nutritional programme; and (vi) not suffering from clin- grade children from disadvantaged schools in Port Eliza-
ical conditions that prevent participation in physical ac- beth, South Africa. Qualitative data revealed that the
tivity, as determined by qualified medical personnel. physical activity materials were well received at the pilot
Children will be excluded from data analyses if (i) they schools.
have a congenital or acquired alteration of the gastro- Participants allocated to the multi-micronutrient sup-
intestinal tract, which could impair absorption of the plementation condition will receive a daily chewable
multi-micronutrient supplements; (ii) they participated tablet containing vitamins and trace elements. The
in food/nutritional programmes in the past 6 months, multi-micronutrient supplement is provided free of
and hence, received regular vitamin and mineral supple- charge by DSM Nutritional Products Ltd. (Basel,
ments; (iii) their parents/guardians did not provide writ- Switzerland; see: www.dsm.com). The exact composition
ten informed consent; and (iv) the children denied oral of the multi-micronutrient supplement is summarised in
assent. Table 1. During school days, the supplement is taken at
Since some parts of the intervention are integrated in schools under the direct supervision of a teacher. To
the compulsory school curriculum, children will be auto- avoid the risk that supplements are exchanged between
matically exposed to physical activity and health/nutri- students or given to other family members during week-
tion education intervention. In fact, physical education is ends or public holidays, no supplements will be provided
foreseen in the curriculum in all three study countries, on non-school days.
not as a separate subject but as part of other (broader) Participants allocated to the physical activity plus
subjects. For instance, in South Africa, physical educa- multi-micronutrient supplementation condition will re-
tion is part of the ‘life orientation’ subject. Nevertheless, ceive both intervention measures, as described above.
physical education is not implemented as it should be in Children who do not receive multi-micronutrient sup-
any of the involved countries. Typically, this slot is used plementation (physical activity only and control condi-
to increase learning time for academic subjects. There- tions) will receive a placebo product. Thus, during
fore, our intervention aims to ensure that the time allo- school days, they will receive a daily chewing tablet,
cated to physical education in the curriculum is used similar in taste and appearance to the multi-
appropriately and filled with meaningful content. micronutrient supplementation and administered to the
In the event that qualified medical personnel identify children from identical packages. The tablet will not
children during the baseline data assessment as having a contain any macronutrients or micronutrients, except
clinical condition that prevents their participation in sugar, citric acid, water and artificial flavour (orange) to
physical activity, we will contact the school principal and mask the taste and to ensure similar appearance.
suggest that these children be removed from the physical
activity intervention. Moreover, as multi-micronutrient Complementary interventions for all participating
supplementation and deworming are additional compo- children
nents, children and their parents/guardians who did not Independently of the study arm allocation, children diag-
provide informed consent can decide whether or not the nosed with helminth infections will receive deworming
child should participate in the multi-micronutrient sup- medication after each data assessment. The treatment
plementation and/or deworming. Finally, all children strategy chosen for each school will follow national and
have the possibility to withdraw from the study anytime international guidelines, including recommendations by
without consequences from these two additional the World Health Organization (WHO) [41]. In brief, in
components. schools where the infection prevalence of soil-
transmitted helminths is below 20%, infected children
Intervention and control conditions will be treated individually; in schools where the infec-
Participants allocated to the physical activity interven- tion prevalence of soil-transmitted helminths is between
tion will receive the so-called KaziKidz physical activity 20% and 50%, all children will be treated once a year;
component (see: www.kazibantu.org). Of note, regular and, finally, in schools were the prevalence of soil-Gerber et al. Trials (2020) 21:22 Page 7 of 17
Table 1 Composition of the multi-micronutrient supplement
No. Nutrient Average per 1 tablet
1 β-carotene (as BetTab 20%S) 3.6 mg
2 Vitamin D 400 IU/10 mcg
3 Vitamin E 9 mg TE
4 Vitamin K 30 mcg
5 Vitamin C 60 mg
6 Vitamin B1 Thiamine 1.1 mg
7 Vitamin B2 Riboflavin 1.3 mg
8 Vitamin B6 Pyriodoxine 0.5 mg
9 Vitamin B12 1.2 mcg
10 Folic acid 200 mcg
11 Niacinamide 8 mg
12 Iron (added as Fe-EDTA) 8 mg
13 Zinc (added as zinc oxide) 5 mg
14 Selenium (added as sodium selenite anhydrous) 20 mcg
15 Iodine (added as potassium iodate) 100 mcg
Notes. Ingredients 1–15 are nutrients and will be produced with an overage to ensure required amounts during the shelf life
Inactive ingredients: sugar, citric acid, sorbitol, non-nutritive sweetener, flavour
Placebo tablets do not contain nutrients, but colorants will be added
Dosage and directions: one tablet daily during the first school lesson
The tablets will be stored in a climate-controlled storage room at the respective research institution and will be provided to school on a fortnightly basis. At
school, the tablets will be stored in locked cupboards in the teachers’ room
transmitted helminth infection is 50% and above, mass carried out by the teachers themselves without external
treatment will be carried out twice a year. We will either assistance.
administer a single 400-mg oral dose of albendazole or a
single 500-mg oral dose of mebendazole. Additionally, Monitoring of compliance with intervention
children infected with S. mansoni will receive praziquan- implementation
tel (single 40 mg/kg oral dose). One of the specific aims of the study is to obtain new in-
All children will additionally benefit from health and sights regarding the possibility to empower schools to
nutritional education lessons. The developed KaziKidz implement sustainable health-promotion measures, in-
teaching material includes a series of classroom-based cluding an appraisal of the implementation quality of
health education lessons to increase awareness of hel- health-promotion measures, if carried out under the dir-
minth infections, how to prevent helminth infections ection of the schools themselves. Using both quantitative
(e.g. hygiene behaviour, adequate sanitation habits and and qualitative research methods, such as the systematic
the importance of consuming clean water and healthy observation of lessons; (semi-)structured interviews with
food). Likewise, nutritional education lessons aim at school principals and parents; and focus group discus-
highlighting the importance of healthy nutrition. sions (FGDs) with teachers, teaching staff members, and
children, the study will shed light on the quality of the
Education and training of the teachers implementation and sustainability of the proposed health
The initial experiences in the DASH study showed that promotion measures, as well as factors affecting the
teachers needed considerable support for the implemen- quality of the implementation and the sustainability of
tation of the physical education lessons. In the planned the programme. Thereof, important insights will result
study, during the initial phase, the intervention will be with regard to the training of the teachers and school
carried out in close collaboration among the teacher- staff, as well as the support needed by the schools to in-
coach, teachers, and school staff to allow sufficient time corporate health-promotion measures in the existing
for capacity building and to empower schools to incorp- structures.
orate the programme in their given structures and to im-
plement the programme with their own resources. Data collection and measures
Hence, teachers will be assisted by a teacher-coach dur- Data collection will take place in the schools. Data as-
ing the first year of the intervention, whereas during the sessment procedures will be based on a series of standar-
second year, the physical activity intervention will be dised, validated and quality-controlled tools. The sameGerber et al. Trials (2020) 21:22 Page 8 of 17
methods will be employed at each measuring occasion Table 2 Overview of parameters assessed in the planned study
(except for the parent questionnaires, which will only Clinical examinations
take place during the baseline assessment). The collected Disease history of children and parents/guardians
data will be double-entered and validated using EpiData Subjective health complaints (15 items)
(version 3.1) and merged into a single database.
Blood pressure (SBP, DBP)
The following parameters are defined as equivalent
primary outcomes: (i) physical activity (7-day accelero- Blood testing
metry), and (ii) multi-micronutrient status (vitamin A, Haemoglobin concentration (Hb)
vitamin D, transferrin and zinc). In our study, physical Blood lipids (TC, HDL-C, LDL-C, TG, Non-HDL, C-HDL ratio)
activity is assessed via self-reports and 7-day accelerome- Blood glucose (HbA1c)
try. Although both methods have advantages and
Micronutrient status (vitamin A, vitamin D, zinc, transferrin)
disadvantages [42, 43], many researchers consider
Cytokines (IL-6)
accelerometer-derived data as the most appropriate way
to validly assess physical activity [44]. This particularly Leptin
applies to children, where the assessment of self- Anthropometric measurements
reported physical activity is complicated by the fact that Body weight and height
some cognitive functions are not yet fully developed. Body composition (body fat)
Multi-micronutrient status, per definition, is a multi- Waist-to-hip ratio
dimensional construct. Given that our supplement con-
Body mass index
tains several (nutritional) ingredients, one can expect
that the product will be effective in terms of multiple Parasitological examinations
outcomes. As highlighted by Bailey et al. [45], iron, iod- Soil-transmitted helminths (Ascaris lumbricoides, hookworm, Trichuris
trichiura)
ine, folate, vitamin A and zinc deficiencies are the most
widespread multi-micronutrient deficiencies and are Schistosoma mansoni
common contributors towards poor growth, intellectual Cognitive function and academic performance
impairment, and increased risk of morbidity. Making a Flanker task (executive function)
decision about whether one nutritional indicator is more School grades
important than another is arbitrary and cannot be con-
Student survey
vincingly substantiated. Therefore, we consider vitamin
Socio-demographic background (sex, ethnicity, home language)
A, vitamin D, transferrin and zinc as equivalent primary
outcomes. Self-reported physical activity
Table 2 provides an overview of all types of data to be Health-related quality of life (KIDSCREEN-10)
collected and the specific parameters that will be Perceived stress (1 item)
assessed either as primary outcomes, secondary out- School satisfaction (1 item)
comes, moderators or control variables.
Perceived academic competence (1 item)
Sleep (6 items)
Clinical examination
A research assistant will assess detailed disease history in a Objective assessment of physical activity
face-to-face interview. Features of disease history will focus 7-day actigraphy
on fevers, abdominal pain, change in bowel movements, Fitness testing
diabetes, and psychosomatic symptoms. Additionally, a 20-m shuttle run test (cardiorespiratory fitness)
qualified nurse will conduct an abdominal examination.
Grip strength test (upper body strength)
For the detection of hypertension, the blood pressure
Parental survey
of each child will be taken three times after the child has
been resting for approximately 5 min, with a 1-min rest Family socioeconomic status
in between the assessments. An Omron M3® digital Dietary intake information (food frequency questionnaire)
blood pressure monitor (Omron Healthcare Europe; Food insecurity
Hoofddorp, The Netherlands) will be used. A cuff size Sleep
appropriate to the arm circumference of the child will
Other variables
be chosen.
Country, school, grade, class, distance/traveling to/from school
Blood testing
Capillary blood will be collected for haematological ana-
lyses. The child’s finger will be pricked once (or ifGerber et al. Trials (2020) 21:22 Page 9 of 17
necessary twice) to collect approximately 10 blood assessment, to void their bladder immediately before the
drops. Haemoglobin (Hb), blood lipid and blood glucose assessment, and to wear only light sport clothing (≤1 kg).
analyses will be performed on the spot (further details Participants will be asked to stand barefoot on the metal
are provided below), with rapid finger prick malaria tests plates of the machine, while being guided by the re-
being done in Côte d’Ivoire and Tanzania. All tests will search assistant to ensure optimal contact according to
be performed with the same measurement devices and the device manufacturer’s instructions. The MC-580 is
are carried out by trained research assistants. Testing also able to assess body weight, which will be measured
cassettes will be disposed immediately after completion to the nearest 0.1 kg. With shoes off, each child will
of the analyses. stand against a stadiometer with the back erect and
shoulders relaxed. Body height will be taken to the near-
Haemoglobin For the detection of anaemia, Hb concen- est 0.1 cm. Sex-specific height or length-for-age and
tration will be measured once with a HemoCue® Hb 301 weight-for-age z scores will be computed from the
system according to the manufacturer’s instructions CDC/WHO growth reference data [47].
(HemoCue AB; Ängelholm, Sweden).
Parasitological examinations
Blood glucose For the measurement of glycated haemo- For parasitological examinations, a researcher will visit
globin (HbA1c) level, a point-of-care (POC) instrument the schools and distribute pre-labelled plastic containers
employing the Afinion test (Alere Technologies, Abbott; to each class for the children to take home and use to
Wädenswil, Switzerland) will be used. Notably, the collect a stool sample. These plastic containers will be
HbA1c level reflects the average plasma glucose concen- returned to the research assistant in the morning of the
tration levels over the previous 8–12 weeks before meas- following day. Further visits may be required to catch up
urement with no prior fasting required. with absent children. To reduce discomfort, paper bags
are provided along with the containers. All stool samples
Blood lipids For the assessment of blood lipid profiles will be processed on the day of collection at the study
(total cholesterol (TC), low-density-lipoprotein choles- site.
terol (LDL-C), high-density-lipoprotein cholesterol Parasitic infections to be detected with the Kato-Katz
(HDL-C) and triglycerides (TG), capillary samples for technique [48] include the three main soil-transmitted
blood lipid will be analysed by the Afinion test (Alere helminths (Ascaris lumbricoides, hookworm and Tri-
Technologies, Abbott; Wädenswil, Switzerland). One churis trichiura), and Schistosoma mansoni. In brief,
drop of blood will be taken up by the test strip and read stool samples (at least 10–15 g) will first be visually ex-
by the machine. Children will be instructed to fast dur- amined for the presence of blood, mucus and diarrhoea.
ing the 3 h prior to the data assessment. Second, duplicate 41.7 mg Kato-Katz thick smears will
be prepared from each stool sample [48]. For quality
Micronutrient status, inflammatory cytokines and control, a random sample of 10% of the Kato-Katz slides
leptin The finger prick technique will also be used to will be re-examined by a senior technician. In case of
prepare dried blood spots to assess children’s micronu- discordant results, the slides will be read a third time,
trient status/deficiencies (concentrations of vitamin A, and the results will be discussed among the technicians
vitamin D, zinc and transferrin) and to determine the in- until agreement has been reached [49, 50]. Parasito-
flammatory cytokine (IL-6) and leptin concentrations. logical status will be established in terms of prevalence
Blood drops will be collected on a filter paper for further and intensity of infection with individual helminth
examination in a specialised laboratory. Dried blood spot species, and the extent of multiparasitism will be
samples on the filter paper will be shipped to the Global determined.
Clinical and Viral Laboratory (Durban, South Africa).
The laboratory was involved in the WHO SAGE study Cognitive function and academic performance
[46] and is a partner institution of the Global Health
Biomarker Lab at the University of Oregon, USA. Executive function Inhibitory control is a core compo-
nent of executive function and will be assessed with a
Anthropometric measurements computer-based version of the Flanker task [51], a stan-
dardised psychological test [52] suitable for repeated
Body weight, body height and body composition Body measures [53]. The task requires participants to respond
composition will be assessed via bioelectrical impedance to the direction of a centrally presented target stimulus,
analysis (BIA) with a wireless body composition monitor while flanking stimuli are facing in the same (congruent
(Tanita MC-580, Tanita Corp.; Tokyo, Japan). The par- trials) or opposite direction (incongruent trials). Per-
ticipants will be asked to fast for 3 h before the data formance is assessed by calculating the mean reactionGerber et al. Trials (2020) 21:22 Page 10 of 17
time for correct responses as well as mean accuracy sep- psychometric properties of this instrument [28]. The
arately for different trial types. Congruent trials are a KIDSCREEN-10 consists of 10 items, which can be used
measure of basic processing speed and attention, to build an overall HRQoL index. Following recom-
whereas incongruent trials assess selective attention and mended procedures, item scores first will be summed up
inhibitory control. to obtain raw scores and then will be transformed into
Rasch person parameter estimates using the available
Academic performance In cooperation with the SPSS software version syntax for each dimension [66].
schools, the end of year marks will be obtained from the These steps will result in T-values with a scale mean of
following subjects: school/home language, first add- 50 and a standard deviation (SD) of 10. Higher mean
itional language, mathematics and life orientation. The scores generally reflect higher HRQoL. To be classified
sum-score of the four subjects will be used to estimate a as ‘normal’, the threshold chosen by the KIDSCREEN
child’s overall academic achievement. developers was the mean, plus or minus half a SD. The
KIDSCREEN scores can be compared with the norm
Student survey scores of an international survey sample of 5754 Euro-
pean children, stratified by sex.
Self-reported physical activity Two self-report instru-
ments will be used to assess physical activity in the
present study [42, 54]. The first instrument is a single- Stress, school satisfaction and perceived academic
item tool taken from the HBSC survey. The exact word- competence Perceived school-related stress, satisfaction
ing of this item is as follows: ‘Physical activity is any with school and perceived academic competence will be
activity that increases your heart rate and makes you get assessed with three items from the HBSC survey. The
out of breath some of the time. Over the past 7 days, on stress measure has been used previously to show evidence
how many days did you engage in such activity?’ for the stress-buffering effects of physical activity in Euro-
Answering options range from 1 to 7 days [55]. A similar pean youngsters [58]. To assess school-related stress, stu-
item has been used in previous research enrolling dents are asked how pressured they feel by the
children [56–58], including the DASH study in South schoolwork they must pursue. Possible answers are as fol-
Africa [28]. lows: not at all, a little, some, and a lot. To measure school
The second instrument is the Physical Activity Ques- satisfaction, students respond to the question of how they
tionnaire for Children (PAQ-C), a 9-item instrument feel about school at present. Possible answers are as fol-
specifically designed for school-aged children [59]. Due lows: ‘I like it a lot’, ‘I like it a bit’, ‘I don’t like it very
to the limited age of our sample and time constraints, much’, and ‘I don’t like it at all’. Finally, perceived aca-
only five items will be included. The PAQ-C consists of demic performance is assessed with the following ques-
a 7-day recall that provides a summary physical activity tion: ‘In your opinion, what does your class teacher(s)
score derived from several items, which are each scored think about your school performance compared to your
on a 5-point Likert-scale (from 1 to 5). Items included classmates?’ Possible answers are as follows: ‘much better
in the present study refer to physical activity accumu- than classmates’, ‘better than classmates’, ‘similar/same as
lated during physical education, recess, after school, in classmates’, and ‘worse than classmates’.
the evening and on weekends. Previous research has
shown that the PAQ-C has acceptable reliability and
convergent validity [60–62]. Furthermore, cut-off Sleep To assess sleep quality, questions from the Pitts-
values have been established which are suitable to dis- burgh Sleep Quality Index (PSQI) [67] will be adapted.
tinguish between those children who accomplish the To screen for sleep disturbances, the three items of the
recommended levels of physical activity (≥60 min of Insomnia Severity Index [68] will ask about difficulty
moderate-to-vigorous physical activity (MVPA) per falling asleep, staying asleep and waking up too early in
day) and children who do not meet these criteria [63]. the morning. Evidence for the reliability and validity of
this measure has been provided previously [69]. To as-
Health-related quality of life The KIDSCREEN-10 will sess further information about sleep quality and daytime
be used to assess children’s HRQoL. The KIDSCREEN- functioning, children will be invited to rate their overall
10 proved to be a valid instrument to assess the psycho- sleep quality and to report how restored they feel in the
social health of children aged 8–18 years in different morning, how tired they feel during the day and how
countries [64]. The construct validity of the KIDSC- exhausted they feel in the evening. Children will also
REEN instrument has been documented in an African provide basic information about their sleep environment
context [65]. Moreover, we have used the KIDSCREEN (e.g. room, type of bed, and people sleeping in the same
in the DASH study, where we found satisfactory room/bed).Gerber et al. Trials (2020) 21:22 Page 11 of 17
Actigraphy as possible with alternating hands. The maximum read-
Objective physical activity will be assessed with an accel- ing, measured to the nearest 1 kg, will be recorded.
erometer device (Actigraph wGT3x-BT; Shalimar, FL,
USA). The devices will be worn around the hip for 7
Parental survey
consecutive days to assess a full week, with a sampling
epoch of 15 s [70]. Time per day spent in moderate
physical activity (MPA; ≥3 metabolic equivalents of task Dietary intake information Information on dietary in-
(MET)) and vigorous physical activity (VPA; ≥6 MET) take will be obtained from the parents/guardians to de-
will be determined based on the raw accelerometry termine the adequacy of child’s intake of macro- and
counts and the ActiLife® computer software (Actigraph; micronutrients. Dietary intake of children will be
Shalimar, FL, USA), with cut-off values derived from assessed using a culturally sensitive food frequency ques-
Freedson et al. [71]. Of note, the ActiGraph accelerome- tionnaire (FFQ) for each country [78, 79]. The FFQ will
ters have been validated for children [72, 73]. be administered to the child’s carer at baseline.
Fitness testing Food insecurity USAID (www.usaid.gov) defines food
security as a situation in which all people at all times
Cardiorespiratory fitness The children’s cardiorespira- have physical and economic access to sufficient food to
tory fitness will be measured with the 20-m shuttle run meet their dietary needs for a productive and healthy
test [74], which is part of the Eurofit fitness testing bat- life. For the purpose of this study, food insecurity will be
tery [75]. Before the start of the test, all children will be measured with a questionnaire based on the Household
told to indicate any body discomfort and anyone who Food Insecurity Access Scale [80], which has been vali-
feels unwell or uncomfortable will not take part in the dated in industrialized countries and LMICs. For ex-
test. The pre-recorded sound signals will be played to ample, the study by Knueppel et al. [81] showed
the children, and they will be able to do a trial run of 2 satisfactory validity and reliability among poor house-
intervals (40 m) under the supervision of a research staff holds in rural Tanzania.
member. Once children are familiar with the test proce-
dures, they will be asked to run back and forth on the
20-m flat course (marked with colour-coded cones) in Sleep To gather information about children’s sleep dur-
groups of 10–15 children, following the pace of the ation, parents/guardians will report the time at which
sound signals. Starting with a running speed of 8.5 km/h, their child goes to bed and wakes up in the morning on
the frequency of the signal increases every minute by school nights and school days.
0.5 km/h. When a child fails to follow the pace in two
consecutive intervals, the stage and the distance com- Socioeconomic status To estimate the SES, parents/
pleted fully will be recorded. The age of the participating guardians will be asked to answer nine items, covering
child and the speed at which the child stopped running household-level living standards, such as infrastructure
will be converted into VO2 max estimates. and housing characteristics (house type, number of bed-
rooms, type of toilet and access to indoor water, indoor
Upper body strength Upper body strength will be de- toilet/bathroom and electricity) and questions related to
termined with the grip strength test, with both right and the ownership of three durable assets (presence of a
left hands. The Saehan hydraulic hand dynamometer working refrigerator, washing machine and car). The di-
(MSD Europe BVBA; Tisselt, Belgium) will be used for chotomized items (0 = poor quality, not available; 1 =
this test. Before the start of the test, the hand span (dis- high quality, available) will be summed up to build an
tance from the tip of the thumb to the tip of the little overall SES index, with higher scores reflecting higher
finger) of the child’s dominant hand will be measured SES. The validity of similar measures was established in
(to the nearest 0.5 cm), and the grip span on the dyna- previous research [82].
mometer will be adjusted accordingly [76, 77]. The out-
door staff will explain to the child how to hold the
dynamometer correctly. The child, while sitting in an Distance from home to school Distance from home to
upright position, should grip the dynamometer with the school and mode of traveling to/from school will be
arm fully extended. During this time, no other parts of taken into consideration as a confounding variable.
the body should touch the dynamometer, and the arm Therefore, we will ask the parents/guardians about their
being tested may not be squeezed against the body. Each living place (township, village and area). Using Google
child will then have three tries, or six tries in total (with maps, we will determine the distance between the resi-
a 30-s rest in between) to grip the dynamometer as hard dence and the school location.Gerber et al. Trials (2020) 21:22 Page 12 of 17
Statistical analyses Req-2018-00608). The intervention study has been
To assess the effects of the intervention, changes in registered in the ISRCTN registry (http://www.isrctn.
outcome variables over the three time points will be com/ISRCTN29534081).
analysed using repeated measures analyses of variances The responsible investigator at each site ensures that
(ANCOVAs), with three between-subject factor groups ethical approval from an appropriately constituted com-
(physical activity intervention: yes/no; multi- petent ethics committee (CEC) is sought for the clinical
micronutrient intervention: yes/no; and weight status: study. The study protocol has been approved in Côte
underweight, normal weight, or overweight/obese) and a d’Ivoire by the Institutional Review Board (IRB) of the
within-subject factor time (baseline, 9 months, and 21 Centre Suisse de Recherches Scientifiques en Côte
months), after controlling for relevant confounders. To d’Ivoire (CSRS; Abidjan, Côte d’Ivoire) and the Comité
take into account the non-independence of the children National d’Ethique et de la Recherche (CNER), reference
within a class, we will examine between-cluster differ- number: 100–18/MSHP/CVESVS-km. Approval has also
ences in potentially relevant confounders, which might been obtained in South Africa from the research ethics
include characteristics of the children (e.g. sex, socioeco- committee of the Nelson Mandela University in Port
nomic status, and ethnicity), class (e.g. class size) and Elizabeth (reference number: H18-HEA-HMS-006) and
the intervention (e.g. compliance with intervention). If the Department of Education of the Eastern Cape Prov-
we find systematic and substantial differences between ince. Moreover, the study protocol has been approved by
the clusters for these variables, the factors will be con- the responsible ethics committee in Tanzania (Ifakara
trolled as covariates. Moreover, we will screen the data Health Institute (IHI–IRB), the National Institute for
for univariate and multivariate outliers before perform- Medical Research (NIMR) and the Tanzania Food and
ing the main analyses in order to exclude students with Drugs Authority (TFDA).
unrealistically high or low values. In case of missing The principal investigator (MG) and local project
values (e.g. when participants drop out), all analyses will leaders (BB, CW, and HM) are allowed to amend the
be performed with and without an intention-to-treat protocol or to provide suggestions for a protocol amend-
[38]. After a thorough dropout analysis, a decision will ment. Should amendments to the approved protocol be
be reached regarding the best suited method to analyse required during the project, these would only be imple-
intention-to-treat effects (e.g. imputation of missing mented after receiving the approval of the CEC.
values) [39]. If significant group or time interactions are
present, Bonferroni-adjusted post-hoc tests will be per- Right to privacy and confidentiality
formed to identify individual differences. Statistical sig- The principal investigator and local project leaders af-
nificance level will be defined at an alpha level of 0.05. firm and uphold the principle of the participants’ rights
Effect size will be calculated according to the recom- to privacy and that they will comply with applicable
mendations of Cohen [83], with 0.49 ≥ d ≥ 0.20 indicating privacy laws. Anonymity of the participants will be guar-
small (negligible practical importance), 0.79 ≥ d ≥ 0.50 in- anteed when presenting the data at national or inter-
dicating medium (moderate practical importance) and national conferences or publishing key findings in the
d ≥ 0.80 indicating large effects (crucial practical import- peer-reviewed literature. Individual participant medical
ance). Additionally, bivariate and multivariate relation- information obtained as a result of this study will be
ships between study variables will be tested using considered confidential, and disclosure to third parties is
correlational analyses, regression analyses or structural prohibited. Participant confidentiality will be further
equation modelling. ensured by utilizing participant identification code num-
bers to correspond to treatment data in the computer
Ethical considerations files. For data verification purposes, authorised represen-
Ethical approval and trial registration tatives of the EKNZ and the respective Human Ethics
The study will be carried out in accordance with the Committee at site may require direct access to parts of
protocol and with principles in the current version of the clinical records relevant to the study, including par-
the Declaration of Helsinki and the guidelines of Good ticipants’ medical histories.
Clinical Practice (GCP) issued by the International Con-
ference of Harmonisation (ICH). Referral to local clinics
The study can only begin once approval from the Children who suffer from severe medical conditions
required authorities has been received. Any add- and/or malnourishment (as diagnosed by a nurse, fol-
itional requirements imposed by the authorities shall lowing national guidelines) will be referred to local
be implemented. Ethical approval has been obtained clinics. If children are infected with malaria at the time
from the ‘Ethikkommission Nordwest- und Zen- of the data assessment, immediate treatment will be of-
tralschweiz’ in Switzerland (EKNZ; reference number: fered to the children.Gerber et al. Trials (2020) 21:22 Page 13 of 17
Incentive for schools specifically, during the entire duration of the study, all
As an incentive for schools, schools will be equipped AEs and all serious adverse events (SAEs) will be col-
with basic sports equipment and a music centre that al- lected, fully investigated and documented in source doc-
lows for the implementation of moving-to-music lessons. uments and CRFs. The study duration encompasses the
Moreover, in South Africa, physical activity-friendly time from when the first participant signs the informed
school environments will be developed through the im- consent until the last protocol-specific procedure has
plementation of simple painted games to encourage the been completed, including a safety follow-up period. In
free play of children. case of any SAE, the participant’s well-being will be
followed up until he or she shows normal laboratory
Data processing and archiving values or vital signs below alert. Project leaders at the
Data will be double-entered, checked, and merged into a site are obliged to document and report the process, in-
single SPSS file. Survey data obtained from the paper dependently of the participant’s termination of study.
and pencil questionnaire will be scanned and entered Each research institution will ensure that the required
automatically (using EvaSys software). Data analysis will insurance coverage is in place for the trial under applic-
be performed with established software packages (e.g. able laws. In case of AEs or SAEs, unblinding of the par-
SPSS, STATA and Mplus). SPSS syntax files will be doc- ticipant is permissible.
umented to assure transparency of the conducted data
analysis and to assure GCP.
Data will be saved electronically. Backup files will be Data monitoring and publication of data
stored regularly on the external cloud Switchdrive@Uni- The trial steering committee (composed of the
versität Basel. The personal data of the participants will sponsor-investigator (MG), the director of the Swiss
be encrypted, and all the data obtained (e.g. hand- Tropical and Public Health Institute (JU), and the
written paper questionnaires and the case report forms principal investigators of the three study countries
(CRFs)) will be used exclusively for scientific research. (BB, CW, HM)) will coordinate data monitoring, in-
The local study leader will keep records in locked cup- terim analysis, and dissemination of the study results
boards, and after 10 years, these records will be through presentations at national and international
destroyed. Completed paper sheets will be locked and conferences and publications in primarily open-access
stored at the respective home institution. Electronic data peer-reviewed journals. The trial steering committee
files will be archived on the database Switchdrive@Uni- will decide which researchers (beyond those listed as
versität Basel. Only authorised investigators will have ac- co-authors in the current study protocol) will have
cess to data files. However, in line with the guidelines access to the final trial dataset. In agreement with the
and open access policies of nationally and internationally other members of the trial steering committee, the
recognised foundations and institutions, the published sponsor–investigator has the right to terminate the
data from our project will be made publicly available (as study prematurely according to certain circumstances,
Additional file 1). including ethical concerns, insufficient participant re-
cruitment, and safety issues. Additional reasons for
Storage of biological material study termination include alterations in accepted clin-
Dried blood spots will be collected on filter paper and ical practice that render the continuation of the trial
stored in a freezer at the home institution. Due to the unwise and evidence of benefit or harm of the experi-
complexity of assaying cytokines in dried blood spot mental intervention. On request of the local ethical
samples, all samples will be shipped to the Global Clin- review boards, an independent data monitoring com-
ical and Viral Laboratory in Durban, South Africa. Thus, mittee will be appointed. The data monitoring board
biological samples from Côte d’Ivoire and Tanzania will will have access to the unblinded interim data and
leave the country conditional to material transfer agree- can make recommendations to the trial steering com-
ments. Dried blood spot analyses will be carried out mittee. Trial auditing is carried out at the end of each
soon thereafter at the laboratory. Samples will be year, whereas annual financial reports will be audited
destroyed upon completion of all required assays. by an external auditor in each study country.
At the end of the study, the results will be communi-
Safety cated to the respective health and education authorities
Research assistants shall report all serious adverse reac- in the study countries and to the involved schools. All
tions and adverse events (AEs) that might occur after intervention materials will be made available to the re-
deworming, finger pricking or multi-micronutrient sup- spective control groups, so that the whole community
plementation immediately to the local study leader and can benefit from this project. Workshops will be offered
principal investigator of the clinical trial. More to all teachers at the involved schools to assist with theYou can also read
